1. Field of the Invention
The present invention relates generally to medical treatment of the diseases that are accompanied by quantitative and qualitative changes of blood extracellular DNA and, more particularly, to a treatment of systemic bacterial, fungal and protozoan infections.
2. Description of the Related Art
Opposite to local infection the systemic infection is accompanied by the presence of pathogenic microorganisms or their components in the blood or tissues and organs other than primary infected area. The systemic infection is life threatening condition frequently accompanied by systemic inflammatory response syndrome (SIRS). Currently the main approach to treatment of systemic bacterial, fungal and protozoan infections is based on antibacterial chemotherapy (see Merck Manual of Diagnosis and Therapy; 16th Edition).
The rapid development of drug resistant bacteria or fungi or protozoa as well as self-protection of bacteria and fungi from therapeutic agents by formation of biofilms are considered as the main barrier for effective antibacterial chemotherapy. (David Davies; Nature Reviews Drug Discovery 2, 114-122, February 2003). Accordingly, the development of new effective, non-toxic methods which might increase the efficacy of antibacterial therapy in the course of systemic infections is an extremely important task.
It is known in the art that DNA of pathogenic microorganism and host DNA, originating from leucocytes is involved in formation and maintaining of purulent masses and biofilms in course of local infection. DNase enzyme has been available in medical practice in the USA for physicians for 40 years, since its discovery in the middle of the 20th century. Ayvazian disclosed the use of parenterally administered pancreatic DNase for destruction of DNA polymer in purulent exudates of patients suffering from pulmonary abscess (J. H. Ayvazian et al., American Review of Tuberculosis and Pulmonary Diseases, 1957, Vol. 76, N1) aiding in the clearing of respiratory airways. Reports indicate that this product had some clinical efficacy, but not enough to justify its widespread use. Bovine pancreatic DNase has been sold under the tradename Dornavac (Merck), but this product was withdrawn from the market mainly due to efficacy concern. Since that DNase enzyme is used almost exclusively to treat purulent masses in cystic fibrosis by inhalation (Pulmozyme; Genentech) or for local wound cleaning from purulent masses (Streptodornase).
Circulating extracellular nucleic acids were discovered more than 60 years ago. However until now they were considered only as useful diagnostic (Moreira V. G. et al., Usefulness of cell-free plasma DNA, procalcitonin and C-reactive protein as markers of infection in febrile patients, Ann Clin Biochem 2010 May; 47(Pt 3): 253-8. Epub 2010 Apr. 26) and research tool (Gal S, Wainscoat J S., Detection and quantitation of circulating Plasmodium falciparum DNA by polymerase chain reaction, Methods Mol. Biol. 2006; 336:155-62; C. O. Morton et al, Dynamics of extracellular release of Aspergillus fumigatus DNA and galactomannan during growth in blood and serum, J Med Microbiol 59 (2010), 408-413).
Circulating extracellular nucleic acids have never been considered as potential therapeutic target in systemic infection. Accordingly, no therapeutic method was developed which efficiently targets extracellular blood DNA in systemic bacterial, fungi or protozoan infection. Thus it makes impossible to take any technical solution as prototype.
As used in this application, the following terms are meant to have the following corresponding definitions.
Deoxyribonuclease (DNase), as used herein, is any enzyme that catalyzes the hydrolytic cleavage of phosphodiester linkages in the DNA backbone.
Extracellular blood DNA number average molecular weight, as used herein, refers to the number average molecular weight is a way of determining the molecular weight of a polymer. Extracellular blood DNA molecules, come in different sizes (chain lengths), so the average molecular weight will depend on the method of averaging. The number average molecular weight is the ordinary arithmetic mean or average of the molecular weights of the individual DNA macromolecules. It is determined by measuring the molecular weight of n polymer molecules, summing the weights, and dividing by n. The number average molecular weight of extracellular blood DNA can be determined by gel electrophoresis. The shift of extracellular blood DNA bands to low-MW areas reflects a decrease in the number average molecular weight and in fact reflects enzymatic cleavage of extracellular blood DNA.